Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essent...
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116946 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0002-4236-0229 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0002-6702-4192 |
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| author | Kellersberger, Katherine A Stall, Brian K Stephanopoulos, Gregory Bar-Sagi, Dafna Han, Jongyoon Rabinowitz, Joshua D Davidson, Shawn M Jonas, Oliver H. Keibler, Mark Andrew Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M Whitman, Matthew A Condon, Kendall Janine Lammers, Alex A Langer, Robert S Vander Heiden, Matthew G. Cima, Michael J. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kellersberger, Katherine A Stall, Brian K Stephanopoulos, Gregory Bar-Sagi, Dafna Han, Jongyoon Rabinowitz, Joshua D Davidson, Shawn M Jonas, Oliver H. Keibler, Mark Andrew Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M Whitman, Matthew A Condon, Kendall Janine Lammers, Alex A Langer, Robert S Vander Heiden, Matthew G. Cima, Michael J. |
| author_sort | Kellersberger, Katherine A |
| collection | MIT |
| description | Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo. |
| first_indexed | 2024-09-23T16:46:09Z |
| format | Article |
| id | mit-1721.1/116946 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:46:09Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1169462022-09-29T21:23:31Z Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors Kellersberger, Katherine A Stall, Brian K Stephanopoulos, Gregory Bar-Sagi, Dafna Han, Jongyoon Rabinowitz, Joshua D Davidson, Shawn M Jonas, Oliver H. Keibler, Mark Andrew Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M Whitman, Matthew A Condon, Kendall Janine Lammers, Alex A Langer, Robert S Vander Heiden, Matthew G. Cima, Michael J. Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Davidson, Shawn M Jonas, Oliver H. Keibler, Mark Andrew Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M Whitman, Matthew A Condon, Kendall Janine Lammers, Alex A Cima, Michael J Langer, Robert S Vander Heiden, Matthew G. Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo. National Science Foundation (U.S.) (Grant T32GM007287) National Cancer Institute (U.S.) (Grant F30CA183474) National Institute of General Medical Sciences (U.S.) (Award T32GM007753) National Institutes of Health (U.S.) (Grant P30CA1405141) National Institutes of Health (U.S.) (Grant R01CA168653) 2018-07-12T18:36:26Z 2018-07-12T18:36:26Z 2016-12 2016-07 2018-07-11T17:52:55Z Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X http://hdl.handle.net/1721.1/116946 Davidson, Shawn M et al. “Direct Evidence for Cancer-Cell-Autonomous Extracellular Protein Catabolism in Pancreatic Tumors.” Nature Medicine 23, 2 (December 2016): 235–241 © 2017 Nature America, Inc., part of Springer Nature https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0002-4236-0229 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0002-6702-4192 http://dx.doi.org/10.1038/NM.4256 Nature Medicine Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Kellersberger, Katherine A Stall, Brian K Stephanopoulos, Gregory Bar-Sagi, Dafna Han, Jongyoon Rabinowitz, Joshua D Davidson, Shawn M Jonas, Oliver H. Keibler, Mark Andrew Hou, Han Wei Luengo, Alba Mayers, Jared R. Wyckoff, Jeffrey Del Rosario, Amanda M Whitman, Matthew A Condon, Kendall Janine Lammers, Alex A Langer, Robert S Vander Heiden, Matthew G. Cima, Michael J. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title | Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title_full | Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title_fullStr | Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title_full_unstemmed | Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title_short | Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors |
| title_sort | direct evidence for cancer cell autonomous extracellular protein catabolism in pancreatic tumors |
| url | http://hdl.handle.net/1721.1/116946 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0002-5410-6543 https://orcid.org/0000-0002-4236-0229 https://orcid.org/0000-0002-8607-1787 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0002-6702-4192 |
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